While advances in antiviral small-molecule therapeutics have been made, the inherently high-rate of viral mutation can rapidly give rise to drug resistance and significantly complicate the treatment and eradication of viral infections. The development of fundamentally new approaches toward therapeutics targeting highly conserved proteins among phylogenetically distant viral strains provides an enhanced genetic barrier to resistance and may constitute a general mechanism for the development of antiviral agents. Viral capsid proteins have highly conserved and critical roles in the viral life cycle of many viruses; however, they represent challenging pharmacological targets and therapeutic approaches, typically involving small-molecule inhibitors, have failed to provide sufficient efficacy. This proposal introduces a fundamentally novel oligonucleotide-based protein inhibition approach that enables the targeted degradation of viral capsid proteins through a highly specific oligonucleotide-protein interaction. In Aim 1 a panel of oligonucleotide aptamers for the targeted degradation of HIV-1 nucleocapsid protein and HBV core protein will be constructed. Using these sets of agents, structure-activity relationship studies will be completed through target protein quantification in order to confirm the ability to degrade capsid proteins, as well as to identify optimized degradation-inducing aptamers. Applying the optimized aptamers, Aim 2 will encompass a therapeutic evaluation of the effect of capsid protein degradation on capsid export and viral gene replication in cellular models of HIV and HBV. Tests that the antiviral efficacy is associated with capsid degradation and not off-target toxicity or an innate immune response will be conducted. In addition, proteomics experiments will confirm the specificity of the protein degrading agents. The degradation-inducing oligonucleotides will be utilized in new cellular delivery methods in order to obviate the need for transfection agents and to set the stage for animal experiments. The expected outcomes of these aims are the development and evaluation of a new technology for the inhibition of viral capsid function through targeted protein degradation. The proposed aims are based on our strong preliminary results in the development of oligonucleotides for the targeting and degrading of proteins, providing an early validation of this novel approach. The proposed research is significant because it provides a highly efficacious approach for complete inhibition of viral capsid functions via programmed protein degradation, thereby overcoming many of the current limitations of nucleic acid-based protein binders. Due to the expected general applicability, this approach will have long-term implications beyond the scope of this proposal.